2.1 Uterine Cancer
Endometrial cancer, or cancer in the lining (endometrium), is the most common type of uterine cancer. Endometrial cancer is the most common female genital cancer and ranks fourth in prevalence behind breast, lung, and colorectal cancers. In 1994, about 46,000 new cases and 10,500 deaths in the U.S. were associated with endometrial cancer. (Boring et al., 1994, CA Cancer J Clin. 44:7–26). The incidence of endometrial cancer in women in the United States is 1% to 2%. It affects mostly postmenopausal women with a median age of 58 years. However, 25% of cases occur in premenopausal women. The incidence of endometrial cancer varies widely among different ethnic groups and countries, and are highest for whites and lowest for blacks and Filipinos.
Increased risk of developing endometrial cancer has been noted in women with increased levels of natural estrogen or those subject to long term hormone replacement therapy. Associated conditions include obesity, diabetes, hypertension, and polycystic ovarian disease. Studies have shown that women taking the drug Tamoxifen to prevent or treat breast cancer have an increased risk of uterine cancer. Other risk factors such as nulliparity (never having carried a pregnancy), infertility, early menarche (onset of menstruation), and late menopause (cessation of menstruation) also increases a woman's risk of being diagnosed with endometrial cancer. Women who have a history of endometrial hyperplasia, endometrial polyps or other benign growths of the uterine lining, postmenopausal women who use estrogen-replacement therapy (specifically if not given in conjunction with periodic progestin), and women with diabetes also fit into the higher risk category.
The most common symptom of uterine cancer is abnormal vaginal and/or uterine spotting or bleeding, such as between periods or after intercourse. Often there is also white or clear vaginal discharge, difficult or painful urination, pain or cramping in the pelvic area, and discomfort during intercourse. However, there are often no symptoms of uterine cancer until the disease is advanced. Even then, symptoms such as loss of appetite, weight loss, fatigue, back or leg pain, leaking of urine or feces from the vagina, and bone fracture are vague and nonspecific and may be caused by other diseases. In advanced cases, endometrial cancer may present like ovarian cancer with ascites, pelvic or abdominal mass, and bowel symptoms. Screening procedures commonly used are pelvic exam, Papanicolaou (Pap) smear, transvaginal ultrasound, and biopsy.
Endometrial cancer usually develops in the uterine fundus and grows into the endometrial cavity, producing an exophytic lesion. It is generally accepted that endometrial hyperplasia results from unopposed estrogen stimulation. The most common histologic type of endometrial cancer is endometrioid carcinoma, accounting for 75% to 80% of case. Squamous differentiation occurs in one third to one half of cases. Well-differentiated lesions correspond to adenoacanthoma, and poor differentiation to adenosquamous carcinoma. Other types of endometrial cancer include papillary serous carcinomas (10%) and clear cell adenocarcinomas (4%).
The staging of endometrial cancer is based on the revised criteria of TNM staging by the American Joint Committee for Cancer (AJCC) published in 1988. Staging is the process of describing the extent to which cancer has spread from the site of its origin. It is used to assess a patient's prognosis and to determine the choice of therapy. The stage of a cancer is determined by the size and location in the body of the primary tumor, and whether it has spread to other areas of the body. Staging involves using the letters T, N and M to assess tumors by the size of the primary tumor (T); the degree to which regional lymph nodes (N) are involved; and the absence or presence of distant metastases (M)—cancer that has spread from the original (primary) tumor to distant organs or distant lymph nodes. Each of these categories is further classified with a number 1 through 4 to give the total stage. Once the T, N and M are determined, a “stage” of I, II, III or IV is assigned. Stage I cancers are small, localized and usually curable. Stage II and III cancers typically are locally advanced and/or have spread to local lymph nodes. Stage IV cancers usually are metastatic (have spread to distant parts of the body) and generally are considered inoperable.
Uterine cancer can be treated with surgery, radiation therapy, chemotherapy, surveillance, adjuvant (additional), or a combination of these treatments. Treatment of uterine cancer depends on the type of cancer, the stage, the size and shape of the tumor, the age and general health of the woman, and her desire for future childbearing.
There are many different types of surgery for uterine cancer. Most women with uterine cancer have surgery to remove the uterus (hysterectomy). The doctor also removes both fallopian tubes and both ovaries (bilateral salpingo-oophorectomy). The doctor may also remove the lymph nodes near the tumor to see if they contain cancer. Radial hysterectomy is associated with a 5-year survival of 90.1%. (Morrow CP and Townsend DE, 1987, Synopsis of Gynecologic Oncology. 3rd ed. New York, N.Y.: John Wiley & Sons Inc., p. 107). A cone biopsy or trachelectomy may be used if the cancerous cells have spread only very slightly beyond the surface cells of the uterine. In certain situations, the ovaries may also be removed but, where possible, they are not taken out in young women as their removal brings on an early menopause. In the most extreme surgery, called a pelvic exenteration, all of the organs of the pelvis, including the bladder and rectum, are removed.
Postoperative radiation is always given in fractionation, to a total dose of 4,500 to 5,000 rads. Even though no survival advantage was shown, radiation therapy appeared to reduce the incidence of pelvic recurrences. Radiation is also used to shrink an especially large tumor prior to surgery or to slow the growth of inoperable tumors using either external beam (similar to an x-ray) or brachytherapy (internal radiation delivered with implanted radioactive seeds). Fatigue is a possible side effect of radiation therapy, but it gradually ceases after treatment is completed.
Short-term chemotherapy, such as hydroxyurea and cisplatin, is used primarily in cases where the disease has spread outside the uterine and where hormonal treatments alone are no longer effective in preventing tumor growth. Potential side effects include nausea and vomiting, loss of hair, low blood cell counts, and fatigue. Many chemotherapeutic drugs have been tried in the past as single agents for the palliation of uterine cancer, but the results were generally disappointing. Nevertheless, the role of chemotherapy in the management of uterine cancer is continually evolving. Oftentimes, chemotherapy with radiation in adjunct to surgery is used. In general, chemotherapy can achieve long-term survival rates of up to 15% to 20%, even in patients with recurrent or metastatic disease (Ali et al., 2000, Oncology 14(8):1223–30). Unfortunately, the high initial response rates to first line chemotherapy does not appear to translate into a survival benefit (Kohno and Kitahara, 2001, Gan To Kagaku Ryoho 28(4):448–53). Moreover, there are many undesirable side effects associated with chemotherapy such as temporary hair loss, mouth sores, anemia (decreased numbers of red blood cells that may cause fatigue, dizziness, and shortness of breath), leukopenia (decreased numbers of white blood cells that may lower resistance to infection), thrombocytopenia (decreased numbers of platelets that may lead to easy bleeding or bruising), and gastrointestinal symptoms like nausea, vomiting, and diarrhea. Active chemotherapeutic agents include cyclosporin A, Taxol, Cisplatin, Carboplatin, Adriamycin, Doxil and Topotecan.
The identification of active chemotherapeutic agents against cancers traditionally involved the use of various animal models of cancer. The mouse has been one of the most informative and productive experimental system for studying carcinogenesis (Sills et al., 2001, Toxicol Letters 120:187–198), cancer therapy (Malkinson, 2001, Lung Cancer 32(3):265–279; Hoffmnan R M., 1999, Invest New Drugs 17(4):343–359), and cancer chemoprevention (Yun, 1999, Annals NY Acad Sci. 889:157–192). Cancer research started with transplanted tumors in animals which provided reproducible and controllable materials for investigation. Pieces of primary animal tumors, cell suspensions made from these tumors, and immortal cell lines established from these tumor cells propagate when transplanted to animals of the same species.
To transplant human cancer to an animal and to prevent its destruction by rejection, the immune system of the animal are compromised. While originally accomplished by irradiation, thymectomy, and application of steroids to eliminate acquired immunity, nude mice that are athymic congenitally have been used as recipients of a variety of human tumors (Rygaard, 1983, in 13th International Cancer Congress Part C, Biology of Cancer (2), pp37–44, Alan R. Liss, Inc., NY; Fergusson and Smith, 1987, Thorax, 42:753–758). While the athymic nude mouse model provides useful models to study a large number of human tumors in vivo, it does not develop spontaneous metastases and are not suitable for all types of tumors. Next, the severe combined immunodeficient (SCID) mice is developed in which the acquired immune system is completely disabled by a genetic mutation. Human lung cancer was first used to demonstrate the successful engraftment of a human cancer in the SCID mouse model (Reddy S., 1987, Cancer Res. 47(9):2456–2460). Subsequently, the SCID mouse model have been shown to allow disseminated metastatic growths for a number of human tumors, particularly hematologic disorders and malignant melanoma (Mueller and Reisfeld, 1991, Cancer Metastasis Rev. 10(3): 193–200; Bankert et al., 2001, Trends Immunol. 22:386–393). With the recent advent of transgenic technology, the mouse genome has become the primary mammalian genetic model for the study of cancer (Resor et al., 2001, Human Molec Genet. 10:669–675).
While surgery, chemotherapeutic agents and radiation are useful in the treatment of uterine cancer, there is a continued need to find better treatment modalities and approaches to manage the disease that are more effective and less toxic, especially when clinical oncologists are giving increased attention to the quality of life of cancer patients. The present invention provides an alternative approach to cancer therapy and management of the disease by using an oral composition comprising yeasts.
2.2 Yeast-Based Compositions
Yeasts and components thereof have been developed to be used as dietary supplement or pharmaceuticals. However, none of the prior methods uses yeast cells which have been cultured in an electromagnetic field to produce a product that has an anti-cancer effect. The following are some examples of prior uses of yeast cells and components thereof:
U.S. Pat. No. 6,197,295 discloses a selenium-enriched dried yeast product which can be used as dietary supplement. The yeast strain Saccharomyces boulardii sequela PY 31 (ATCC 74366) is cultured in the presence of selenium salts and contains 300 to about 6,000 ppm intracellular selenium. Methods for reducing tumor cell growth by administration of the selenium yeast product in combination with chemotherapeutic agents is also disclosed.
U.S. Pat. No. 6,143,731 discloses a dietary additive containing whole β-glucans derived from yeast, which when administered to animals and humans, provide a source of fiber in the diet, a fecal bulking agent, a source of short chain fatty acids, reduce cholesterol and LDL, and raises HDL levels.
U.S. Pat. No. 5,504,079 discloses a method of stimulating an immune response in a subject utilizing modified yeast glucans which have enhanced immunobiologic activity. The modified glucans are prepared from the cell wall of Saccharomyces yeasts, and can be administered in a variety of routes including, for example, the oral, intravenous, subcutaneous, topical, and intranasal route.
U.S. Pat. No. 4,348,483 discloses a process for preparing a chromium yeast product which has a high intracellular chromium content. The process comprises allowing the yeast cells to absorb chromium under a controlled acidic pH and, thereafter inducing the yeast cells to grow by adding nutrients. The yeast cells are dried and used as a dietary supplement.
Citation of documents herein is not intended as an admission that any of the documents cited herein is pertinent prior art, or an admission that the cited documents are considered material to the patentability of the claims of the present application. All statements as to the date or representations as to the contents of these documents are based on the information available to the applicant and does not constitute any admission as to the correctness of the dates or contents of these documents.